US2025388599A1PendingUtilityA1
Tricyclic pi3k inhibitor compounds and methods of use

Assignee: GENENTECH INCPriority: Dec 16, 2010Filed: Aug 28, 2025Published: Dec 25, 2025
Est. expiryDec 16, 2030(~4.4 yrs left)· nominal 20-yr term from priority
Inventors:Jennafer Dotson Robert Andrew Heald Timothy Heffron Graham Elgin Jones Sussie Lerche Krintel Neville James Mclean Chudi Ndubaku Alan G. Olivero Laurent Salphati Lan Wang Binqing Wei
C07K 2317/24C07K 16/22C07D 498/20C07D 491/147A61K 2039/505A61K 39/3955A61K 31/5386A61K 31/5383A61K 31/5377C07D 498/14C07D 487/14C07D 495/14C07D 491/14C07D 471/14C07D 471/22A61P 3/10A61P 9/00A61P 7/00A61P 43/00A61P 37/04A61P 37/02A61P 37/00A61P 35/02A61P 35/00A61P 31/12A61P 29/00A61P 25/00A61P 1/16C07D 519/00C07D 498/22
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Claims
Abstract

Tricyclic PI3k inhibitor compounds of Formula I with anti-cancer activity, anti-inflammatory activity, or immunoregulatory properties, and more specifically with PI3 kinase modulating or inhibitory activity are described. Methods are described for using the tricyclic PI3K inhibitor compounds of Formula I for in vitro, in situ, and in vivo diagnosis or treatment of mammalian cells, organisms, or associated pathological conditions. Formula I compounds include stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof. The dashed lines indicate an optional double bond, and at least one dashed line is a double bond. The substituents are as described.
Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A compound selected from Formula I: 
       
         
           
           
               
               
           
         
         and stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof, wherein: 
         the dashed lines indicate an optional double bond, and at least one dashed line is a double bond; 
         X 1  is S, O, N, NR a , CR 1 , C(R 1 ) 2 , or —C(R 1 ) 2 O—; 
         X 2  is C, CR 2  or N; 
         X 3  is C, CR 3  or N; 
         A is a 5, 6, or 7-membered carbocyclyl or heterocyclyl ring fused to X 2  and X 3 , optionally substituted with one or more R 5  groups; 
         R a  is H, C 1 -C 12  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, —(C 1 -C 12  alkylene)-(C 3 -C 12  carbocyclyl), —(C 1 -C 12  alkylene)-(heterocyclyl having 3-20 ring atoms), —(C 1 -C 12  alkylene)-C(═O)-(heterocyclyl having 3-20 ring atoms), —(C 1 -C 12  alkylene)-(C 6 -C 20  aryl), and —(C 1 -C 12  alkylene)-(heteroaryl having 5-20 ring atoms), where alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, —CH 3 , —CH 2 CH 3 , —C(CH 3 ) 3 , —CH 2 OH, —CH 2 CH 2 OH, —C(CH 3 ) 2 OH, —CH 2 OCH 3 , —CN, —CH 2 F, —CHF 2 , —CF 3 , —CO 2 H, —COCH 3 , —COC(CH 3 ) 3 , —CO 2 CH 3 , —CONH 2 , —CONHCH 3 , —CON(CH 3 ) 2 , —C(CH 3 ) 2 CONH 2 , —NO 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHCOCH 3 , —NHS(O) 2 CH 3 , —N(CH 3 )C(CH 3 ) 2 CONH 2 , —N(CH 3 )CH 2 CH 2 S(O) 2 CH 3 , ═O, —OH, —OCH 3 , —S(O) 2 N(CH 3 ) 2 , —SCH 3 , —S(O) 2 CH 3 , cyclopropyl, cyclobutyl, oxetanyl, morpholino, and 1,1-dioxo-thiopyran-4-yl; 
         R 1 , R 2 , and R 3  are independently selected from H, F, Cl, Br, I, —CH 3 , —CH 2 CH 3 , —C(CH 3 ) 3 , —CH 2 OH, —CH 2 CH 2 OH, —C(CH 3 ) 2 OH, —CH 2 OCH 3 , —CN, —CF 3 , —CO 2 H, —COCH 3 , —COC(CH 3 ) 3 , —CO 2 CH 3 , —CONH 2 , —CONHCH 3 , —CON(CH 3 ) 2 , —C(CH 3 ) 2 CONH 2 , —NO 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHCOCH 3 , —NHS(O) 2 CH 3 , —N(CH 3 )C(CH 3 ) 2 CONH 2 , —N(CH 3 )CH 2 CH 2 S(O) 2 CH 3 , ═O, —OH, —OCH 3 , —S(O) 2 N(CH 3 ) 2 , —SCH 3 , —S(O) 2 CH 3 , cyclopropyl, cyclobutyl, oxetanyl, morpholino, and 1,1-dioxo-thiopyran-4-yl; 
         R 4  is selected from C 6 -C 20  aryl, heterocyclyl having 3-20 ring atoms and heteroaryl having 5-20 ring atoms, each of which are optionally substituted with one or more groups R 6  groups independently selected from F, Cl, Br, I, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —CH 2 CH 3 , —CH 2 CN, —CN, —CF 3 , —CH 2 OH, —CO 2 H, —CONH 2 , —CONH(CH 3 ), —CON(CH 3 ) 2 , —NO 2 , —NH 2 , —NHCH 3 , —NHCOCH 3 , —OH, —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —SH, —NHC(═O)NHCH 3 , —NHC(═O)NHCH 2 CH 3 , —NHC(═O)NHCH(CH 3 ) 2 , —NHS(O) 2 CH 3 , —N(CH 3 )C(═O)OC(CH 3 ) 3 , —S(O) 2 CH 3 , benzyl, benzyloxy, morpholinyl, morpholinomethyl, and 4-methylpiperazin-1-yl; and 
         R 5  is independently selected from C 1 -C 12  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, —(C 1 -C 12  alkylene)-(C 3 -C 12  carbocyclyl), —(C 1 -C 12  alkylene)-(heterocyclyl having 3-20 ring atoms), —(C 1 -C 12  alkylene)-C(═O)-(heterocyclyl having 3-20 ring atoms), —(C 1 -C 12  alkylene)-(C 6 -C 20  aryl), and —(C 1 -C 12  alkylene)-(heteroaryl having 5-20 ring atoms); or two geminal R 5  groups form a 3, 4, 5, or 6-membered carbocyclyl or heterocyclyl ring, where alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, —CH 3 , —CH 2 CH 3 , —C(CH 3 ) 3 , —CH 2 OH, —CH 2 CH 2 OH, —C(CH 3 ) 2 OH, —CH 2 OCH 3 , —CN, —CH 2 F, —CHF 2 , —CF 3 , —CO 2 H, —COCH 3 , —COC(CH 3 ) 3 , —CO 2 CH 3 , —CONH 2 , —CONHCH 3 , —CON(CH 3 ) 2 , —C(CH 3 ) 2 CONH 2 , —NO 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHCOCH 3 , —NHS(O) 2 CH 3 , —N(CH 3 )C(CH 3 ) 2 CONH 2 , —N(CH 3 )CH 2 CH 2 S(O) 2 CH 3 , ═O, —OH, —OCH 3 , —S(O) 2 N(CH 3 ) 2 , —SCH 3 , —S(O) 2 CH 3 , cyclopropyl, cyclobutyl, oxetanyl, morpholino, and 1,1-dioxo-thiopyran-4-yl; 
         mor is selected from: 
       
       
         
           
           
               
               
           
         
         optionally substituted with one or more R 7  groups independently selected from F, Cl, Br, I, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —C(CH 3 ) 3 , —CH 2 OCH 3 , —CHF 2 , —CN, —CF 3 , —CH 2 OH, —CH 2 OCH 3 , —CH 2 CH 2 OH, —CH 2 C(CH 3 ) 2 OH, —CH(CH 3 )OH, —CH(CH 2 CH 3 )OH, —CH 2 CH(OH)CH 3 , —C(CH 3 ) 2 OH, —C(CH 3 ) 2 OCH 3 , —CH(CH 3 )F, —C(CH 3 )F 2 , —CH(CH 2 CH 3 )F, —C(CH 2 CH 3 ) 2 F, —CO 2 H, —CONH 2 , —CON(CH 2 CH 3 ) 2 , —COCH 3 , —CON(CH 3 ) 2 , —NO 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHCH 2 CH 3 , —NHCH(CH 3 ) 2 , —NHCH 2 CH 2 OH, —NHCH 2 CH 2 OCH 3 , —NHCOCH 3 , —NHCOCH 2 CH 3 , —NHCOCH 2 OH, —NHS(O) 2 CH 3 , —N(CH 3 )S(O) 2 CH 3 , ═O, —OH, —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —SH, —NHC(═O)NHCH 3 , —NHC(═O)NHCH 2 CH 3 , —S(O)CH 3 , —S(O)CH 2 CH 3 , —S(O) 2 CH 3 , —S(O) 2 NH 2 , —S(O) 2 NHCH 3 , —S(O) 2 N(CH 3 ) 2 , and —CH 2 S(O) 2 CH 3 . 
       
     
     
         2 . The compound of  claim 1 , wherein the compound is selected from Formulas Ia-n: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 1 , wherein such compound is selected from:
 Ia, Ib, Id, Ij and In.   
     
     
         4 . The compound of  claim 1 , wherein Formula Ta is selected from the structures: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       where the A heterocyclyl ring is optionally substituted with one or more R 5  groups. 
     
     
         5 . The compound of  claim 1 , wherein Formula Ia is selected from the structures: 
       
         
           
           
               
               
           
         
       
       where the A heterocyclyl ring is optionally substituted with one or more R 5  groups. 
     
     
         6 . The compound of  claim 1 , wherein Formula Ia is: 
       
         
           
           
               
               
           
         
       
       where the A heterocyclyl ring is optionally substituted with one or more R 5  groups. 
     
     
         7 . The compound of  claim 1 , wherein Formula If is selected from the structures: 
       
         
           
           
               
               
           
         
       
       where the A heterocyclyl ring is optionally substituted with one or more R 5  groups. 
     
     
         8 . The compound of  claim 1 , wherein R 4  is phenyl substituted with one or more groups selected from F, Cl, Br, I, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CN, —CF 3 , —CH 2 OH, —CO 2 H, —CONH 2 , —CONH(CH 3 ), —CON(CH 3 ) 2 , —NO 2 , —NH 2 , —NHCH 3 , —NHCOCH 3 , —OH, —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —SH, —NHC(═O)NHCH 3 , —NHC(═O)NHCH 2 CH 3 , —NHS(O) 2 CH 3 , —N(CH 3 )C(═O)OC(CH 3 ) 3 , and —S(O) 2 CH 3 . 
     
     
         9 . The compound of  claim 1 , wherein R 4  is an optionally substituted bicyclic heteroaryl group selected from 1H-indazole, 1H-indole, indolin-2-one, 1-(indolin-1-yl)ethanone, 1H-benzo[d][1,2,3]triazole, 1H-pyrazolo[3,4-b]pyridine, 1H-pyrazolo[3,4-d]pyrimidine, 1H-benzo[d]imidazole, 1H-benzo[d]imidazol-2(3H)-one, 1H-pyrazolo[3,4-c]pyridine, 1H-pyrrolo[2,3-c]pyridine, 3H-imidazo[4,5-c]pyridine, 7H-pyrrolo[2,3-d]pyrimidine, 7H-purine, 1H-pyrazolo[4,3-d]pyrimidine, 5H-pyrrolo[3,2-d]pyrimidine, 2-amino-1H-purin-6(9H)-one, quinoline, quinazoline, quinoxaline, isoquinoline, isoquinolin-1(2H)-one, 3,4-dihydroisoquinolin-1(2H)-one, 3,4-dihydroquinolin-2(1H)-one, quinazolin-2(1H)-one, quinoxalin-2(1H)-one, 1,8-naphthyridine, pyrido[3,4-d]pyrimidine, and pyrido[3,2-b]pyrazine. 
     
     
         10 . The compound of  claim 1 , wherein optionally substituted R 4  is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       where the wavy line indicates the site of attachment. 
     
     
         11 . The compound of  claim 9 , wherein R 4  is 1H-indazol-4-yl. 
     
     
         12 . The compound of  claim 1 , wherein R 4  is an optionally substituted monocyclic heteroaryl group selected from 2-furanyl, 3-furanyl, 2-imidazolyl, 4-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-pyrazinyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 2-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrrolyl, 3-pyrrolyl, 2-thienyl, 3-thienyl, 5-tetrazolyl, 1-tetrazolyl, 2-tetrazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-triazolyl, and 1-triazolyl. 
     
     
         13 . The compound of  claim 12 , wherein R 4  is 2-aminopyrimidin-5-yl. 
     
     
         14 . The compound of  claim 1 , wherein optionally substituted R 4  is selected from: 
       
         
           
           
               
               
           
         
       
       where the wavy line indicates the site of attachment. 
     
     
         15 . The compound of  claim 1 , wherein one or more R 5  groups are independently selected from F, Cl, Br, I, —CH 3 , —CH 2 CH 3 , —C(CH 3 ) 3 , —CH 2 OH, —CH 2 CH 2 OH, —C(CH 3 ) 2 OH, —CH 2 OCH 3 , —CN, —CH 2 F, —CHF 2 , —CF 3 , —CO 2 H, —COCH 3 , —COC(CH 3 ) 3 , —CO 2 CH 3 , —CONH 2 , —CONHCH 3 , —CON(CH 3 ) 2 , —C(CH 3 ) 2 CONH 2 , —NO 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHCOCH 3 , —NHS(O) 2 CH 3 , —N(CH 3 )C(CH 3 ) 2 CONH 2 , —N(CH 3 )CH 2 CH 2 S(O) 2 CH 3 , ═O, —OH, —OCH 3 , —S(O) 2 N(CH 3 ) 2 , —SCH 3 , —S(O) 2 CH 3 , cyclopropyl, cyclobutyl, oxetanyl, morpholino, and 1,1-dioxo-thiopyran-4-yl. 
     
     
         16 . The compound of  claim 1 , wherein two geminal R 5  groups form cyclopropyl, cyclobutyl, cyclopentyl, tetrahydrofuryl, tetrahydropyranyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, cyclohexyl, morpholino, or 1,1-dioxo-thiopyran-4-yl. 
     
     
         17 . The compound of  claim 1 , wherein mor is 
       
         
           
           
               
               
           
         
       
       where the wavy line indicates the site of attachment, optionally substituted with one or more R 7  groups independently selected from F, Cl, Br, I, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —C(CH 3 ) 3 , —CH 2 OCH 3 , —CHF 2 , —CN, —CF 3 , —CH 2 OH, —CH 2 OCH 3 , —CH 2 CH 2 OH, —CH 2 C(CH 3 ) 2 OH, —CH(CH 3 )OH, —CH(CH 2 CH 3 )OH, —CH 2 CH(OH)CH 3 , —C(CH 3 ) 2 OH, —C(CH 3 ) 2 OCH 3 , —CH(CH 3 )F, —C(CH 3 )F 2 , —CH(CH 2 CH 3 )F, —C(CH 2 CH 3 ) 2 F, —CO 2 H, —CONH 2 , —CON(CH 2 CH 3 ) 2 , —COCH 3 , —CON(CH 3 ) 2 , —NO 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHCH 2 CH 3 , —NHCH(CH 3 ) 2 , —NHCH 2 CH 2 OH, —NHCH 2 CH 2 OCH 3 , —NHCOCH 3 , —NHCOCH 2 CH 3 , —NHCOCH 2 OH, —NHS(O) 2 CH 3 , —N(CH 3 )S(O) 2 CH 3 , ═O, —OH, —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —SH, —NHC(═O)NHCH 3 , —NHC(═O)NHCH 2 CH 3 , —S(O)CH 3 , —S(O)CH 2 CH 3 , —S(O) 2 CH 3 , —S(O) 2 NH 2 , —S(O) 2 NHCH 3 , —S(O) 2 N(CH 3 ) 2 , and —CH 2 S(O) 2 CH 3 . 
     
     
         18 . A compound of  claim 1 , wherein the compound is selected from the group consisting of:
 1-[4-(3a,8-dimethyl-7-morpholin-4-yl-3,3a,8,8a-tetrahydro-2h-1-oxa-4,6,8-triaza-cyclopenta[a]inden-5-yl)-phenyl]-3-ethyl-urea,   5-(6,6-dimethyl-4-morpholino-8,9-dihydro-6h-[1,4]oxazino[3,4-e]purin-2-yl)-4-methylpyrimidin-2-amine,   5-(6,6-dimethyl-4-morpholino-8,9-dihydro-6h-[1,4]oxazino[3,4-e]purin-2-yl)pyrimidin-2-amine,   5-(6,6-dimethyl-4-morpholino-8,9-dihydro-6h-[1,4]oxazino[3,4-e]purin-2-yl)-4-(trifluoromethyl)pyridyl-2-amine,   5-(4-morpholino-8,9-dihydro-7h-[1,3]oxazino[2,3-e]purin-2-yl)pyrimidin-2-amine,   5-(4-morpholino-6,7,8,9-tetrahydropyrido[2,1-e]purin-2-yl)pyrimidin-2-amine,   5-(4-morpholino-6,7, 8,9-tetrahydropyrido[2,1-e]purin-2-yl)pyridin-2-amine,   5-(4-morpholino-8,9-dihydro-6h-[1,4]oxazino[3,4-e]purin-2-yl)-4-(trifluoromethyl)pyridyl-2-amine,   5-(4-morpholino-7,8-dihydro-6h-pyrrolo[2,1-e]purin-2-yl)pyrimidin-2-amine,   6,6-dimethyl-4-morpholino-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purine,   5-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)pyridin-2-amine,   5-(4-morpholino-8,9-dihydrospiro[[1,3]oxazino[2,3-e]purine-7,1′-cyclopropane]-2-yl)pyrimidin-2-amine,   5-(4-morpholino-8,9-dihydro-6h-[1,4]oxazino[3,4-e]purin-2-yl)pyrimidin-2-amine,   5-(4-morpholino-8,9-dihydrospiro[[1,4]oxazino[3,4-e]purine-6,3′-oxetane]-2-yl)pyrimidin-2-amine,   5-(7,7-dimethyl-4-morpholino-8,9-dihydro-7h-[1,3]oxazino[2,3-e]purin-2-yl)pyrimidin-2-amine,   5-(4-morpholino-6-(trifluoromethyl)-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)pyridin-2-amine,   5-(6,6-(hexadeuterio)dimethyl-4-morpholino-8,9-dihydro-6h-[1,4]oxazino[3,4-e]purin-2-yl)pyrimidin-2-amine,   (S)-5-(6-ethyl-6-methyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)pyrimidin-2-amine,   5-(6,6,9-trimethyl-4-morpholino-6h-[1,4]oxazino[3,4-e]purin-2-yl)pyrimidin-2-amine,   (R)-5-(6-ethyl-6-methyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)pyrimidin-2-amine,   5-(1-morpholin-4-yl-5,6,8a,9-tetrahydro-8h-7,10-dioxa-2,4,4b-triaza-phenanthren-3-yl)-pyrimidin-2-ylamine,   5-((S)-6-Morpholin-4-yl-2,3,3a,4-tetrahydro-1H-5-oxa-7,9,9b-triaza-cyclopenta[a]naphthalen-8-yl)-pyrimidin-2-ylamine,   4-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)aniline,   1-(4-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)phenyl)-3-methylurea,   6,6-dimethyl-4-morpholino-2-(1H-pyrazol-4-yl)-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purine,   4-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)pyridin-2-amine,   6,6-dimethyl-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purine,   3-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)phenol,   2-(1H-indazol-5-yl)-6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purine,   6,6-dimethyl-2-(2-(4-methylpiperazin-1-yl)12yridine-4-yl)-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purine,   N-(2-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)phenyl)methanesulfonamide,   6,6-dimethyl-4-morpholino-2-(6-morpholinopyridin-3-yl)-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purine,   2-(1-benzyl-1H-pyrazol-4-yl)-6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purine,   2-(2-isopropoxypyridin-3-yl)-6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purine,   N-(2-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)phenyl)acetamide,   2-(3,5-dimethyl-1H-pyrazol-4-yl)-6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purine,   5-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)pyridine-2-ol,   6-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)pyridine-3-amine,   (R)-5-(4-morpholino-6-(trifluoromethyl)-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)pyrimidin-2-amine,   (S)-5-(4-morpholino-6-(trifluoromethyl)-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)pyrimidin-2-amine,   2-(1-ethyl-1H-pyrazol-4-yl)-6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purine,   4-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)-N,N-dimethylbenzamide,   tert-butyl 4-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)phenyl(methyl)carbamate,   2-(3-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)phenyl)acetonitrile,   6,6-dimethyl-4-morpholino-2-(3-morpholinophenyl)-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purine,   6,6-dimethyl-4-morpholino-2-(3-(morpholinomethyl)phenyl)-8,9-dihydro-6H-[11,4]oxazino[3,4-e]purine,   2-(3-(benzyloxy)phenyl)-6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purine,   2-(1-isobutyl-1H-pyrazol-4-yl)-6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purine,   6,6-dimethyl-2-(6-(4-methylpiperazin-1-yl)13yridine-3-yl)-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purine,   2-(1H-indazol-4-yl)-6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purine,   4-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)benzonitrile,   5-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)nicotinamide,   5-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)-N-methylpicolinamide,   2-(4-(benzyloxy)phenyl)-6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purine,   3-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)-N,N-dimethylaniline,   6,6-dimethyl-2-(4-(4-methylpiperazin-1-yl)phenyl)-4-morpholino-8,9-dihydro-6H-[11,4]oxazino[3,4-e]purine,   6,6-dimethyl-4-morpholino-2-(4-(piperidin-1-yl)phenyl)-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purine,   N-(5-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)pyridine-2-yl)acetamide,   5-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)picolinamide,   6-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)pyridine-3-ol   (4-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)phenyl)(4-methylpiperazin-1-yl)methanone,   N-cyclopropyl-3-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)benzamide,   5-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)-N,N-dimethylpyrazin-2-amine,   1-(4-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)phenyl)-3-ethylurea,   1-(4-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)phenyl)-3-isopropylurea,   2-(2-aminopyrimidin-5-yl)-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purine-6,6-diyl)dimethanol,   2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholino-8,9-dihydropyrazino[2,1-e]purin-6(7H)-one,   5-(8,8-Dimethyl-1-morpholin-4-yl-5, 8-dihydro-6H-7-oxa-9-thia-2,4-diaza-fluoren-3-yl)-pyrimidin-2-ylamine,   2-(1H-indazol-4-yl)-4-morpholino-6-(trifluoromethyl)-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purine,   3-(4-morpholino-6-(trifluoromethyl)-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)phenol,   5-(4-((2S,6R)-2,6-dimethylmorpholino)-6,6-dimethyl-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)pyrimidin-2-amine,   5-(4-(2,2-dimethylmorpholino)-6,6-dimethyl-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)pyrimidin-2-amine,   N-(5-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)pyrimidin-2-yl)acetamide,   5-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6,6-dimethyl-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)pyrimidin-2-amine,   2-(2-aminopyrimidin-5-yl)-6-methyl-4-morpholino-6,7-dihydropyrazino[2,1-e]purin-8(9H)-one,   5-(6,7-dimethyl-4-morpholino-6,7,8,9-tetrahydropyrazino[2,1-e]purin-2-yl)pyrimidin-2-amine; and   (5-(8,8-Dimethyl-1-morpholin-4-yl-5,6-dihydro-8H-7-oxa-2,4,4b-triaza-fluoren-3-yl)-pyrimidin-2-ylamine.   
     
     
         19 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier, glidant, diluent, or excipient. 
     
     
         20 . A method of treating cancer in a patient, the method comprising administering to said patient a therapeutically effective amount of a compound of  claim 1  wherein the cancer is breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, non-small cell lung carcinoma (NSCLC), small cell carcinoma, lung adenocarcinoma, bone, colon, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidney carcinoma, renal, pancreatic, myeloid disorders, lymphoma, hairy cells, buccal cavity, naso-pharyngeal, pharynx, lip, tongue, mouth, small intestine, colon-rectum, large intestine, rectum, brain and central nervous system, Hodgkin&#39;s or leukemia.
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